HIV (Human Immunodeficiency Virus), a retrovirus, is a causative virus of AIDS (Acquired Immunodeficiency Syndrome). HIV targets CD4 positive cell groups such as helper T cell, macrophage and dendritic cell and destroys these immunocompetent cells to cause immunodeficiency.
Accordingly, a pharmaceutical agent that eradicates HIV in the body or suppresses its growth is effective for the treatment or prevention of AIDS.
HIV possesses a bimolecular RNA gene in a core protein, which is covered with an envelope protein. The RNA codes for several enzymes (protease, reverse transcriptase, integrase) and the RNA has translated reverse transcriptase and integrase in the core, as well as protease inside and outside the core.
HIV attaches to and invades a host cell, becomes uncoated, and releases a complex of RNA and integrase into the cytoplasm. From the RNA, DNA is transcribed by reverse transcriptase, and a full length double stranded DNA is produced. The DNA is imported into the nucleus of the host cell and integrated by integrase into the DNA of the host cell. The integrated DNA is converted to an mRNA by polymerase of the host cell. Various proteins necessary for forming a virus are synthesized from the RNA by HIV protease, and a virus particle is finally formed, which then undergoes budding and is released from the host cell.
These virus specific enzymes are considered to be essential for the growth of HIV. These enzymes are drawing attention as the target of the development of antiviral agents, and several anti-HIV agents have been already developed.
For example, zidovudine (AZT), didanosine, lamivudine (3TC), and the like have been already on the market as reverse transcriptase inhibitors, and indinavir and nelfinavir as protease inhibitors.
In addition, a multiple drug combination therapy concurrently using these pharmaceutical agents has been employed. For example, a combined use of two reverse transcriptase inhibitors (zidovudine and didanosine) has been used clinically. A combined use of three agents of reverse transcriptase inhibitors (zidovudine and lamivudine) and a protease inhibitor (nelfinavir) and other pharmaceutical agents have also been clinically applied. Such multiple drug combination therapy is becoming a mainstream of AIDS therapy (see, e.g., Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adlescent. Aug. 13, 2001).
However, some of these pharmaceutical agents are known to cause side effects such as liver function failure, central nervous disorders (e.g., vertigo), etc. In addition, acquisition of resistance to a pharmaceutical agent causes a problem. Even worse, emergence of an HIV that shows multiple drug resistance in a multiple drug combination therapy has been known.
Under the circumstances, a further development of a novel pharmaceutical agent, particularly a development of an anti-HIV agent based on a new mechanism, has been desired. Specifically, it has been a goal to develop an anti-HIV agent having an integrase inhibitory activity, because an integrase characteristic of retrovirus is an essential enzyme for the growth of HIV.
Nevertheless, there is a need to identify effective integrase inhibitors.
The present invention overcomes one or more of these needs and provides further related advantages.
Known compounds different from Compound A of the present invention are described in the following.
WO02/0704865 describes the following compounds (B1), (B2), and the like as anti-HIV agents having an integrase inhibitory activity (see WO02/0704865 p. 118, Example I-62, p. 203, Example I-152).

In addition, WO02/36734 describes the following compound (B3), and the like as anti-HIV agents having an integrase inhibitory activity (see WO02/36734, p. 106, Ex. 3).

Moreover, WO02/55079 describes the following compound (B4), and the like as anti-HIV agents having an integrase inhibitory activity (see WO02/055079, p. 79, Ex. 1).

However, these publications do not include (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (“Compound A”) disclosed in the present specification, or any description suggestive thereof.
U.S. Pat. No. 3,472,859 describes the following compound (B5), and the like as antibacterial agents or antimicrobial agents (see U.S. Pat. No. 3,472,859, column 11, line 10).

In addition, JP-A-48-26772 describes the following compound (B6), and the like as compounds having an antibacterial activity (see, e.g., JP-A-48-26772, p. 6, Example 9; KYUSHU KYORITSU UNIVERSITY, Memoirs Department of Engineering, No. 14, pp. 21-32, March 1990; Memoirs Kyushu Inst. Tech. (Eng.) No. 14, pp. 13-16, 1984).

As dehydrogenase inhibitors, moreover, the following compound (B7), and the like have been pharmacologically evaluated (see Journal of Medicinal Chemistry, table 1, vol. 15, No. 3, pp. 235-237, 1972).

In addition, JP-A-2002-534416 (patent family: WO00/40561, U.S. Pat. No. 6,248,739, EP1140850) describes the following compound (B8), and the like as synthetic intermediates for compounds having an antiviral activity (see JP-A-2002-534416, p. 141, compound 60).

JP-A-2002-534417 (patent family: WO00/40563, U.S. Pat. No. 6,248,736, EP1140851) also describes the following compound (B9), and the like as synthetic intermediates for compounds having an antiviral activity (see JP-A-2002-534417, p. 34, compound 18).

Moreover, WO01/98275 (patent family: U.S. 2001/103220) also describes the following compound (B10), and the like as synthetic intermediates for compounds having an antiviral activity (see WO01/98275, p. 39, line 29).

Furthermore, JP-A-4-360872 (patent family: U.S. Pat. No. 5,985,894, EP498721B1) describes the following compound (B11), and the like as compounds having an antagonistic action against anti-angiotensin II receptor (see JP-A-4-360872, p. 64, Table 1)).
